Pathogenic mechanisms in highly active anti‐retroviral therapy‐induced hepatotoxicity: role of phosphodieaterase 4 and ER‐stress (653.7)

HIV protease inhibitors (HIV‐PIs) are the major components of HAART and have been successfully used in the treatment of HIV‐1 infection in the past two decades. However, it has been shown that HIV‐PIs induce endoplasmic reticulum (ER) stress response and subsequent activation of unfolded protein response leading to dys‐regulation of hepatic lipid metabolism and hepatotoxicity. Our recent work shows that PDE4/cAMP metabolism plays a significant role in alcohol‐induced hepatic steatosis and injury. Hence in the present study, we examined the mechanisms underlying HIV‐PI induced hepatic ER stress and toxicity with a particular emphasis on PDE4 family of enzymes. The effects of clinically used HIV‐PIs (Ritonavir and Lopinavir) were examined both in a rat hepatoma cell line as well as rat primary hepatocytes. These studies demonstrated that PIs led to a significant loss of hepatocyte survival. Notably, inhibition of PDE4 by a specific PDE4‐inhibitor, rolipram, markedly attenuated hepatotoxicity induced by PIs. Mechanistic role of PDE4 showed that PDE4 inhibition significantly decreases the expression of the ER stress related proteins CHOP, ATF‐4 and ‐3 induced by PIs. Furthermore, examination of the PDE4/cAMP‐regulated downstream signaling demonstrated the involvement of Exchange proteins activated by cAMP (EPAC). Specifically, EPAC cAMP analogue downregulated the expression of the PI‐induced ER‐stress genes. These data identify a pathogenic/mechanistic role for PDE4 regulated cAMP‐EPAC in the development of HIV‐PI induced ER‐stress leading to hepatic steatosis and injury. Grant Funding Source : Supported by NIH, DOD and Veterans Administration